19-hydroxy-3-aza-a-homo-steroids

ABSTRACT

IN WHICH OR4 REPRESENTS A FREE, ESTERIFIED OR ETHERIFIED HYDROXYL GROUP AND A PROCESS OF MANUFACTURING SAME. THE NEW COMPOUNDS ARE STRONG LOCAL ANESTHETICS.   (CH3-CH(-CH3)-(CH2)3-CH(-CH3)-)(H--)   (CH3-CO-)(R4-O--), (HO-CH2-CO-)(R4-O--),   (R4-O-)(H--), (R4-O-)(LOWER ALIPHATIC HYDROCARBON--)   WHICH MAY CONTAIN A DOUBLE BOND IN THE 4,4A, OR THE 5,6POSITION, WHEREIN R1=H OR LOWER ALKYL R2O=A FREE, ESTERIFIED OR EHTERIFIED HYDROXYL GROUP AND R3=FREE OR KETALIZED OXO GROUP   NAPHTH(1,2-D)AZEPINE   3-R1,5A-(R2-O-CH2-),7A-(CH3-),8-(R3=)CYCLOPENTA(5,6)   THE INVENTION RELATES TO NOVEL COMPOUNDS OF THE FORMULA

United States Patent ()ffice 3,706,736 Patented Dec. 19, 1972 US. Cl.260239 BB Claims ABSTRACT OF THE DISCLOSURE The invention relates tonovel compounds of the formula RqOCHr CH3 Jr Cd which may contain adouble bond in the 4,40, or the 5,6- position, wherein R =H or loweralkyl R O=a free, esterified or etherified hydroxyl group and R =free orketalized oxo group 'H lower aliphatic hydrocarbon ?Ha CH OH C O O I (I1 in which 0R represents a free, esterified or etherified hydroxyl groupand a process of manufacturing same. The new compounds are strong localanesthetics.

The present invention is concerned with the manufacture of new19-hydroxy-3-aza-A-homo-steroids, preferably of the androstane, pregnaneor cholestane series, especially of those of the general formula RzOCHwhich may contain a double bond in the -4u,5- or 5,6-position and inwhich R represents hydrogen or a lower alkanoyl residue, R 0 stands fora free, esterified or etherifield hydroxyl group, preferably for a loweralkanoyl-oxy group or a lower alkoxy residue which may be substituted byphenyl residues, and R represents a free or ketalized oxo group, forexample the ethylenedioxy group or a ,8- positioned free, esterified oretherified hydroxyl group together with a hydrogen atom or with a loweraliphatic hydrocarbon residue or an a-positioned hydrogen atom ora-positioned free, esterified or etherified hydroxyl group together withan acetyl or hydroxyacetyl group or derivatives thereof or antZ-POSltlOIlCd hydrogen atom together with the l',5'-dimethyl-hexylgroup.

An esterified hydroxyl group is especially a hydroxyl group esterifiedwith an aliphatic, alicyclic, araliphatic or aromatic or heterocycliccarboxylic acid with l-20 carbon atoms, for example, formic,methylcarbonic acid, acetic, trifiuoroacetic, trimethylacetic,propionic, capric, decanoic, undecylenic, hexahydrobenzoic,cyclopentylpropionic, phenylpropionic, benzoic or furancarboxylic acid.An etherified hydroxy group is especially etherified with an aliphatic,cycloaliphatic, araliphatic or heterocyclic alcohol, such as a loweralkanol or with a furanyl or pyranyl alkanol.

Suitable lower aliphatic hydrocarbon residues are, for example, loweralkyl such as methyl, ethyl, propyl or isopropyl residues, lower alkenylsuch as vinyl, ally or methallyl residues, or lower alkinyl such asethinyl or propinyl residues.

The term lower as used above or below with reference to hydrocarbon oralkanoyl residues indicates such residues containing 1-5 carbon atoms.

The new compounds possess valuable pharmacological properties. Interalia, they act strongly on the central nervous system, similarly to theaction of the salamander alkaloids. Furthermore, they display a stronglocal anaesthetic activity and may therefore be used in human andveterinary medicine. They are also valuable intermediates for themanufacture of the salamander alkaloids and their derivatives. Thus, forexample, appropriate androstane compounds may be used for themanufacture of the highly active salamander alkaloid cycloneosamandioneor of its derivatives.

The new compounds are obtained when a compound of the formula which maycontain a double bond in the 4,5 or the 5,6 position but does notcontain a further free oxo group and where one of the radicals R and R"stands for an oxo group and the other for two hydrogen atoms and R and Rhave the above meanings, is reacted with hydroxylamine or with a saltthereof, the resulting oxime is subjected to the Beckmann rearrangementand the oxo group in position 4 or 2 and, if desired, a possibly presentdouble bond in position 4a,5 or 5,6 is/are reduced and, if desired, anesterified hydroxyl group present is liberated, a free hydroxyl group isoxidized to the oxo group, a protected oxo group present is convertedinto the free oxo group, an oxo group present is reduced to the hydroxylgroup or removed by reduction, and/or, if desired, at any stage the azagroup is acylated, especially acetylated, and/ or a resulting base isconverted into a salt or quaternary ammonium salt thereof.

Preferably the starting materials of the formula given above, wherein Rrepresents an oxo group contain the double bond, if present, in theposition 5,6 or wherein R" stands for the oxo group, the double bond, ifpresent, or in 4,5-position.

These reactions are carried out in known manner. Thus, for example, theoxime is obtained by reacting the oxo compound with hydroxylamine or asalt thereof, such as hydroxylamine hydrochloride, in the presence of atertiary base, for example pyridine. The oxime is rearranged ac- RzOCHicording to Beckmann into the aza compound with a strong Lewis acid, forexample sulphuric, hydrochloric acid, phosphorus pentachloride,sulphurylchloride or thionylchloride, preferably in an inert solventsuch as dioxane. From the 2-oxo-compound there is generally obtained amixture of the Z-aza and the 3-aza-compound from which the3-aza-derivative can be isolated by chromatography after first havingacylated the mixture.

Starting from a 3-oxo-compound having a double bond in 4,5-positionthere is always obtained th'e 3-aza-compound, whereas a compound havingno double bond in 4,5-position gives a mixture of the 3- and4-aza-compound, which is separated after acetylation by chromatography.

The 4- or 2-oxo group is reduced, for example, by means oflithium-aluminium hydride and the possibly present double bond in the5,6-psition preferably with hydrogen in the presence of a platinumcatalyst. This gives rise to a mixture of the 505- and SB-isomers whichlend themselves well to the usual separation by chromatography. A doublebond which may be present in 4,5-position is reduced preferably by meansof hydrogen in the presence of a paladium catalyst. There is thusobtained only the 5a-dihydro compound.

Any ester or protective groups, such as ketals, present in the resultingaza-A-homo compounds can be split hydrolytically and free hydroxylgroups may be oxidized to 0x0 groups. On the other hand, processproducts containing free hydroxyl groups can be converted into theiresters in known manner, for example by acylation with an hydride orhalide of a carboxylic acid. The starting materials used are known orcan be manufactured by known processes.

The invention includes also any variant of the process in which anintermediate obtained at any stage of the process is used as startingmaterial and the remaining process steps are performed or in whichstarting materials are formed under the reaction conditions or in whichthe reactants may be used in the form of their salts.

The new compounds of the Formula I may be used as medicaments, forexample in the form of pharmaceutical preparations containing them inconjunction or admixture with a pharmaceutical organic or inorganicsolid or liquid excipient suitable for enteral or parenteraladministration. Suitable excipients are substances that do not reactwith the new compounds, for example water, gelatin, lactose, starches,stearyl alcohol, magnesium stearate, talcum, vegetable oils, benzylalcohols, gums, propyleneglycol, polyalkyleneglycols, cholesterol orother known medicinal excipients. The pharmaceutical preparations maybe, for example, tablets drages or capsules, or in liquid formsolutions, suspensions or emulsions, or in form of ointments or creams.They may be sterilized and/or contain assistants such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, or buffers. They may furthercontain other therapeutically valuable substances. The pharmaceuticalpreparations are formulated in the usual manner.

The new compounds may also be used in veterinary medicine, for examplein one of the forms mentioned above or in form of feedingstutfs oradditives to feedingstuffs, using, for example, the conventionalextenders and diluents, or feedingstuffs respectively.

The following examples illustrate the invention without restricting itin any way. The infrared spectra have been recorded in chloroform.

EXAMPLE 1 A mixture of 200 mg. of 2-oxo-17-ethylenedioxy-19-triphenyl-methoxy-A -IOa-androstane and 200 mg. of hydroxylaminehydrochloride in ml. of pyridine is boiled for 2 hours, then evaporatedand the residue is taken up in methylenechloride and chromatographed onsilica gel (Merck, 0.05-0.2 mm.), eluted with a 10:1-mixture of benzeneand e y ace a e, and the eluate is eva orated to furnish 2oximino-17-ethylenedioxy-19-tri-phenylmethoxy A 10oz androstene meltingat 235236 C. [a] =-30 (c.=0.57 in chloroform). Its infrared spectrumcontains bands at 3580 and 1 450 cmf A solution of 5.1 g. of the aboveoxime in 25 ml. of absolute dioxan is mixed at 5 C. with 1.5 ml. ofthionyl chloride. The mixture is kept for 2 hours at 20 C., then pouredinto an ice-cooled aqueous sodium bicarbonate solution and extractedwith methylenechloride. Chromatography on silica gel and elution with a1:2-mixture of benzene+ethyl acetate furnishes a mixture from which the2-oxo-3-aza-17-ethylenedioxy A homo 19 triphenylmethoxy-A lOa-androsteneis separated by further chromatography on a stepped column. After tworecrystallizations from acetone+petroleum ether the product melts at229230 C. [a] =--13 (c.=0.53 in chloroform). Its infrared spectrumcontains bands at 3410, 1665 and 1450 cm.-

700 mg. of the above compound with 1.4 g. of lithiumaluminium hydride in250 ml. of dioxan are boiled for 20 hours, then water is dropped inwhile cooling with ice, the precipitated inorganic phase is filteredoff, washed with methylenechloride and the filtrate is evaporated undervacuum. The crude product is acetylated with acetic anhydride andpyridine for 1 hour on a waterbath and then chromatographed on silicagel, to yield N-acetyl- 3-aza-l7-ethylenedioxy 19 triphenylmethoxy-A-IOa-A- homoandrostene which, after crystallization fromacetone+petroleum ether, melts at 150-155 C. [a] =--25 (c.=0.47 inchloroforma), and N-acetyl-3-aza-17-ethylenedioxy 19-acetoxy-A-10a-A-homo-androstene melting at 112-114" C. [a] =-12 (c.=0.50 inchloroform).

18 mg. of N-acetyl-S-aza-17-ethylendioxy-l9-acetoxy- A-l0a-A-homo-androstene in 2 ml. of 5% aqueous acetic acid are boiled for1 hour at 90 C., then evaporated under vacuum, chromatographed on silicagel and the unitary eluates are crystallized from ether-I-hexane. Theresulting N-acetyl 3 aza-17-oxo-19-acetoxy-A -l0a-A- homo-androstenemelts at 144-145 C. [oc] =-|63 (c.=0.35 in chloroform). The infraredspectrum of this compound contains bands at 1735 (shoulder), 1630 and1250 cmf A mixture of 330 mg. of N-acetyl-3-aza-17-ethylenedioxy 19triphenylmethoxy A 10a-A-homo-androstene, 2 ml. of acetic anhydride and0.5 ml. of boron trifiuoride etherate is kept for 5 minutes at roomtemperature, then poured into an ice-cooled aqueous sodium bicarbonatesolution, extracted with methylenechloride, and the extract is dried andevaporated. The resulting crude product is once more heated for 1 hourwith 2 ml. of 5% acetic acid to remove the ketal group completely fromit. After evaporation, chromatography and recrystallization N-acetyl 3aza-17-oxo-19-acetoxy-A -10u-A-homo-androstene melting at 144145 C. isobtained; according to the mixed melting point, infrared spectrum andthinlayer chromatogram it is identical with the product dey scribedabove.

The starting material used in this example may be prepared, forinstance, as follows:

1 gram of 2-oxo-l7fi-acetoxy-A -10u-androstene in ml. of tetrahydrofuranand 2 g. of tri-tertiary butoxylithium aluminium hydride are refluxedfor 2 hours, 5% aqueous acetic acid is added and the whole is worked upas usual. 20: hydroxy 17,8 acetoxy-A -10a-androstene melts at 200 C.after two recrystallizations from acetone+petroleum ether. [a] =68(c.=0.69 in chloroform). Bands in the infrared spectrum at 3610, 1724and 1250 cmr' 600 mg. of lead tetraacetate and 250 mg. of calciumcarbonate are dried for 1 hour under a high vacuum, then suspended in 20ml. of cyclohexane and boiled for 10 minutes. The boiling mixture ismixed with 130 g. of iodine and then with mg. of2a-hydroxy-17/8-acetoxy- A -10u-androstene and boiled for another 1%hours while being irradiated with two incandescent lamps (210 watt),

then filtered through cottonwool, the solution is taken up in ethylacetate, washed with thiosulphate and saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. Chromatographyon silica gel in benzene+ethyl acetate 9:1 and crystallization fromacetone +petroleum ether furnishes 2ot,19-oxido-17B-acetoxy- 19-oxo-A-10u-androstene melting at 180 C. [a] +64 (c.=0.27 in chloroform).

1.7 grams of this compound are hydrolyzed in 140 ml. of saturatedmethanolic potassium carbonate solution overnight at 20 C. The batch isthen acidified (pH=5) with dilute hydrochloric acid and evaporated andWorked up, to furnish 2a,19-oxido-17t3-hydroxy-10-oxo-A -IOa-androstenewhich melts at 225 C. after crystallization from acetone+petroleumether. [a] =+88 (c.:0.50 in chloroform) 1.35 grams of this product aredissolved in 70 ml. of acetone and 1.2 ml. of 8 N-chromium trioxide in 8N- sulphuric acid are added at C. After 1 /2 hours the excess oxidant isdecomposed by adding a few drops of methanol. Usual working up furnishes2zx,l9-OXid017,l9- dioxo-A -a-androstene which melts at 208 C. aftercrystallization from acetone+petroleum ether. [a] +175 (c.=0.66 inchloroform).

1.2 grams of this compound with 300 mg. of p-toluenesulphonic acid in amixture of 200 ml. of benzene and 30 ml. of ethyleneglycol are boiledfor 24 hours on a water separator, then poured into an ice-cooledaqueous sodium bicarbonate solution and taken up in methylenechloride,washed and dried and the extract is evaporated to yield 2e,19-oxido 17ethylenedioxy-19-oxo-A -wet-androstene which melts at 233 C. aftercrystallization from acetone+petroleum ether. [a] =+36 (c.=0.75 inchloroform).

750 mg. of this product are boiled for 3 hours with 1.1 g. of lithiumaluminium hydride in 100 ml. of tetrahydrofuran. Usual working upfurnishes 2a,l9-dihydroxy-l7- ethylenedioxy-A -mot-androstene melting at224 C. [a] =68 (c.=0.31 in chloroform).

316 mg. of this compound are boiled for 7 hours with 500 mg. oftriphenylchloromethane in 30 ml. of pyridine, then evaporated and workedup in the usual manner. Chromatography in a 10:1-mixture ofbenzene;+ethyl acetate and crystallization from acetone+petroleum etherfurnishes Ze-hydroxy-17-ethylenedioxy-19-triphenylmethoxy- Ame-androstene melting at 211212 C. [a] =-33 (c.=0.58 in chloroform).

While cooling 10 ml. of pyridine, 1.3 g. of chromium trioxide is added,then 780 mg. of the resulting 2a-hydroxy compound in 10 ml. of pyridineare added at 0 C. and the whole is kept for 18 hours at C., thenfiltered through a glass suction filter and the filtrate is taken up inethyl acetate. Usual working up and chromatography in a 10:1-mixture ofbenzene and ethyl acetate and crystallization from acetone+petroleumether furnishes 2-oxo-17-ethylenedioxy 19 triphenylmethoxy-A-l0otandrostene melting at 215 C. [a] =2O (c.=0.77 in chloroform).

EXAMPLE 2 A mixture of 1764 mg. of 2-oxo-17-ethy1enedioxy-19-triphenylmethoxy-5u-10nt-androstane and 1760 mg. of hydroxylaminehydrochloride in 80 ml. of pyridine is boiled for 2 hours, thenevaporated and worked up in the usual manner. The resulting crudeproduct is chromatographed on silica gel (Merck, 0.050.2 mm.) and elutedwith a 10:1-mixture of benzene and ethyl acetate. The eluate isevaporated and recrystallized from acetone+petroleum ether, to furnish2-oxirnino-17-ethylenedioxy-19-triphenylmethoxy 5a,10u androstanemelting at 210 C. [u] =-16 (c.=0.42 in chloroform).

A solution of 1460 mg. of this compound in 8 ml. of dioxan is mixed at 5C. with 1 m1. of thionylch'loride. The mixture is kept for 2 hours at 20C., then poured into an ice-cooled aqueous sodium bicarbonate solution,taken up in methylenechloride and the extract is dried over sodiumsulphate and evaporated, chromatographed on silica gel and eluted withethyl acetate. Two crystallizations from acetone+petroleum ether furnish2-oxo-3- aza-17-ethylenedioxy 19 triphenylmethoxy-Sa,loot-A-homo-androstane melting at 267269 C. [u] =|-2 (c.=0.46 in chloroform).

A mixture of 275 ml. of this compound and 0.6 g. of lithium aluminiumhydride in 100 ml. of dioxan is boiled for 20 hours, then water isdropped in while cooling with ice, the precipitated inorganic phase isfiltered off, Washed with methylenechloride and the filtrate isevaporated to dryness. The resulting mixture is acetylated andchromatographed in the usual manner, to yield N-acetyl-3-aza-l7-ethylenedioxy-19-triphenylmethoxy 50,100t A-homo-androstane melting at202 C. [u] '=+18 (c.=0.45 in chloroform) andN-acetyl-B-aza-17-ethylenedioxy-19-acetoxy-A-homo-5a,mot-androstanemelting at 132134 C. [a] =+52 (c. =0.16 in chloroform).

N-acetyl-S-aza 17 ethylenedioxy l9 acetoxy-5vz,- mot-androstane can behydrolyzed with acetic acid to form N-acetyl-3-aza-l7-oxo-l9-acetoxy5ot,l0a A homoandrostane as described in Example 1 which melts at 171-172 C. after crystallization from acetone+petroleum ether. [a] ='+135(c.0.41 in chloroform).

In the manner described in Example 1 N-acetyl-3-aza- 17-ethylenedioxy 19tI'iphenylmethOXy-Sa,10a-A-homoandrostane can be converted intoN-acetyl-3-aza-l7-oxo- 19-acetoxy-5u,IOa-A-homo-androstane which isidentical with the compound described above.

mg. of N-acetyl-3-aza 17 oxo-19-acetoxy-5u,10a- A-h0m0-andr0stane arehydrolyzed overnight at room temperature in 10 ml. of saturatedmethanolic potassium carbonate solution. Usual working up andchromatography on silica gel in ethylacetate+methanol 9:1 furnishesamorphous N-acetyl-3-aza-19-hydroxy A homo-Se waandrostane whoseinfrared spectrum contains bands at 3580, 1730 and 1625 cm.-

The starting material used in this example may be prepared, for example,thus 500 mg. of 2a-hydroxy 17,8 acetoxy-M-androstane in 75 ml. ofethanol are exhaustively hydrogenated in the presence of mg. ofpalladium carbon catalyst (5% Pd). The catalyst is filtered Off, thefiltrate evaporated under vacuum and the crude product is taken up inmethylenechloride and filtered through alumina (neutral, activity III)and chromatographed on silica gel, to furnish the oily2ot-hydroxy-l7fl-acetoxy-5a,10u-androstane whose infrared spectrumcontains bands at 3600, 1725 and 1255 cm.

500 mg. of this compound are reacted with lead tetraacetate and iodinein cyclohexane as described in Example 1, then worked up andchromatographed on silica gel (Merck, 0.05-0.2 mm). Recrystallization ofthe eluate from acetone+petroleum ether furnishes 20:,19-0Xid0-17B-acetoxy-19-oxo-5u,wot-androstane melting at 174-175 C. [a] =+37 (c.=0.40in chloroform).

This compound is hydrolyzed by the method described in Example 1 toyield 2a,19-oxido-17;3-hydroxy-19-oxo- 50,100c-311dl'08t31'1fi meltingat 162-163 C. [a] =-+47 (c.=0.46 in chloroform), then oxidized to20:,19-OX1C10- 17,19-dioxo-5u,wot-androstane melting at 201 C. [a] +131(c.=0.45 in chloroform), then converted into2a,19-oxido-l7-ethylenedioxy 19 oxo 5u,10u androstane melting at 229230C. [a] =+19 (c.=0.48 in chloroform), reduced with lithium-aluminiumhydride to form 2a,19-dihydroxy 17 ethylenedioxy-5a,IOa-androstanemelting at 194-196 C. [a] =14 (c.=0.56 in chloroform), which is thenreacted with triphenylchloromethane to form 2a-hydroxy-17-ethylenedioxyl9 triphenylmethoxy-5a,lOct-androstane and then oxidized to form2-oxo-17-ethylenedioxy 19 triphenylmethoxy-5ot,- mix-androstane meltingat 224 C. [a] (c.=0.5'0 in chloroform).

7 EXAMPLE 3 2 grams of 3-oxo-17B,l9-diacetoxy-A -androstene and 2 g. ofhydroxylamine hydrochloride in 40 ml. of pyridine are heated for 1%hours at 90 C. and then evaporated under vacuum. The residue is taken upin methylenechloride, the solution washed neutral, dried over sodiumsulphate and evaporated, to furnish 3-oximino-17 S-19-diacetoxy-M-androstene as an amorphous product whose infrared spectrumcontains bands at 3580, 1730 and 1240 cmf A solution of 11.5 g. of thisoxime in 50 ml. of dioxan is mixed with 2 ml. of thionylchloride. Thereaction mixture is heated for 1 hour at 60 C., then neutralized withice-cold aqueous sodium bicarbonate solution and extracted withmethylenechloride. The extract is washed neutral, dried and evaporated,twice chromatographed on silica gel (Merck, 0.05-0.2 mm.) and elutedwith a 10:1-mixture of ethyl acetate and methanol and recrystallizedfrom acetone+petroleum ether, to yield 3- aza 4 oxo 17 9,19diacetoxy-A-homo-A -androstene melting at 195 C. [a] =+53 (c.=0.49 inchloroform). Its infrared spectrum contains bands at 3420, 1730, 1655and 1240 cmr 3 grams of this product are exhaustively hydrogenated inthe presence of 1 g. of palladium carbon catalyst in 200 ml. of ethanol.The catalyst is filtered off, the filtrate evaporated and the residuerecrystallized from acetone+ petroleum ether. The resulting3-aza-4-oxo-175,19-diacetoxy-A-homo-Sa-androstane has the double meltingpoint of 133/165 C. [a] =3 (c.=0.39 in chloroform). Its infraredspectrum contains bands at 3410, 1730, 1665 and 1245 cmr 320 mg. of thisproduct are boiled for 20 hours with 600 mg. of lithium -aluminiumhydride in 100 ml. of dioxan. Then, while cooling with ice, water isdropped in, the precipitated inorganic phase is filtered off, washedwith methylenechloride, and the filtrate is evaporated to dryness, tofurnish crude 3-aza-17fi,19-dihydroxy-A-homo- Set-androstane. 100 mg. ofthis product are acetylated for 1 hour in a waterbath andchromatographed on silica gel. Elution with ethyl acetate furnishesamorphous N-acetyl- 3-aza-l7fi,19-diacetoxy-A-homo-5a-androstane whoseinfrared spectrum contains bands at 1730, 1625 and 1250 cm.-

50 mg. of this product are hydrolyzed overnight in ml. of saturatedmethanolic potassium carbonate solution. Two crystallisations fromacetone+petroleum ether furnish N acetyl 3aza-175,19-dihydroxy-A-homo-5aandrostane melting at 244 to 246 C. [a]--23 (c.=0.44 in ethanol). Its infrared spectrum contains bands at3500-3100 and 1620 cmr EXAMPLE 4 A solution of 5.1 g. of3-oxo-17,8,19-diacetoxy-5B- androstane in 70 ml. of pyridine is boiledfor 2 hours with 5.1 g. of hydroxylamine hydrochloride, then evaporatedto dryness, taken up in methylenechloride, washed neutral andchromatographed on silica gel (Merck, 0.05- 0.2 mm.), eluted with a2:1-mixture of benzene-i-ethyl acetate, evaporated and the residue istwice recrystallized from ether+petroleum ether. The resulting3-oximino- 175,19 diacetoxy 5B androstane melts at 142 C. [a] =+39(c.=0.94 in chloroform). Its infrared spectrum contains bands at 3580,1730 and 1250 crnr 2.1 grams of this product are dissolved in ml. ofdioxan and mixed at 5 C. with 1 ml. of thionylchloride. The mixture iskept for 2 hours at C., then poured into ice-cooled aqueous sodiumbicarbonate solution and extracted with methylenechloride. The extractis washed, dried over sodium sulphate and evaporated. Afterchromatography on silica gel and elution with ethyl acetate a product isobtained which melts at 204-206 C. After three recrystallizations fromether-l-petroleum ether the melting 8 point rises to 205-207 C. [oz]=+29 (c.=0.53 in chloroform).

2 grams of this mixture of 3-aza-4-oxoand 3-oxo-4-aza-17B,19-diacetoxy-A-homo-5 8-androstane are boiled for 20 hours with4 g. of lithium-aluminium hydride in 800 ml. of dioxane. 'Ihen whilecooling with ice, water is dropped in, the precipitated inorganic phaseis filtered off, rinsed with methylene chloride and the filtrate isevaporated, to yield after acylation a mixture of N-acetyl-3-azaandN-acetyl 4 aza-17B,19-diacetoxy-A-homo-SB-androstane which melts at144-145 C. after two recrystallizations from acetone+petroleum ether.[a] =-|28 (c.=0.40 in chloroform). Its infrared spectrum contains bandsat 1730, 1625 and 1250 cmf We claim:

1. 19-hydroxy-3-aza-A-homo-wet-steroids of the formula which may containa double bond in the 4a,5 or in the 5,6-position, in which formula Rrepresents hydrogen or a lower alkanoyl radical, R 0 stands for a free,esterified or etherified hydroxyl group, and R for a free or ketalizedoxo group or a fit-positioned free, esterified or etherified hydroxylgroup together with a hydrogen atom or with a lower alkyl, loweral-kenyl or lower alkinyl group or an a-positioned hydrogen atom or ana-positioned free, esterified or etherified hydroxyl group together withan acetyl or hydroxyacetyl group or an a-positioned hydrogen atomtogether with the 1',5'-dimethylhexyl group, each of said ester groupsbeing derived from a carboxylic acid with 1-20 carbon atoms and each ofsaid ether groups being derived from a lower alkanol, a furanol or apyranol.

2. N acetyl 3 aza 17-ethylendioxy-19-triphenylmethoxy-A-10a-A-homo-androstene.

3. N acetyl 3 aza 17 ethylendioxy-l9-acetoxy-A 10a-A-homo-androstene.

4. N acetyl 3 aza 17 oxo-19-acetoxy-A -10a-A- homo-androstene.

5. N acetyl 3 aza 17-ethylenedioxy-l9-acetoxy-A- homo-5a, 1Oat-androstane.

6. N acetyl 3aza-17-ethylenedioxy-19-triphenylmethoxy-A-homo-Sa,loot-androstane.

7. N acetyl 3 aza 17 0x0-19-acetoxy-A-homo-5a- IDOL-androstane.

8. N-acetyl 3 aza-19-hydroxy-A-homo-5a,wot-androstane.

9. N acetyl 3 aza 1713,19 diacetoxy-A-homo-Saandrostane.

10. N acetyl 3 aza 17 8,19 dihydroxy-A-homo-5aandrostane.

References Cited UNITED STATES PATENTS 4/1970 Sallay 260-239 OTHERREFERENCES ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

